Progenitor Cell Therapy in a Porcine Acute Myocardial Infarction Model Induces Cardiac Hypertrophy, Mediated by Paracrine Secretion of Cardiotrophic Factors Including TGFβ1
Progenitor Cell Therapy in a Porcine Acute Myocardial Infarction Model Induces Cardiac Hypertrophy, Mediated by Paracrine Secretion of Cardiotrophic Factors Including TGFβ1
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DOI：
10.1089/scd.2007.0214
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发表时间：
2008-10-01
影响因子：
4
通讯作者：
Caplice, Noel M.
中科院分区：
文献类型：
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作者：
Doyle, Brendan;Sorajja, Paul;Caplice, Noel M.
内皮祖细胞（EPC）的施用是梗死后心脏修复的一种有前景的疗法。然而，对心肌重塑产生明显有益作用的机制尚不清楚。在急性心肌梗塞的猪模型中，我们研究了培养修饰的外周血单核细胞（以下称为猪 EPC）的混合群的治疗效果。猪 EPC 的分离方法与之前在人类细胞治疗研究中收获 EPC 所采用的方法相同。此外，在体外和体内评估了这些细胞分泌的旁分泌因子的治疗效果。与对照相比，冠状动脉内注射自体猪 EPC 与 2 个月时梗塞区域质量增加和局部心室收缩功能改善相关。使用源自自体 EPC 的条件培养基治疗与梗塞区域质量和功能的类似改善效果相关。梗塞区域的组织学分析显示，与对照组相比，EPC 和条件培养基治疗组的心肌细胞大小显着增加。旁分泌 EPC 效应也在纯心肌制剂中得到了验证，其中缺乏成纤维细胞、神经元和血管成分的心肌细胞在暴露于相同的条件培养基时通过增加细胞质量直接做出反应。条件培养基分析显示 TGF beta 1 水平升高（人为 267.3 +/- 11.8 pg/ml，猪为 57.1 +/- 6.1 pg/ml），这是公认的心脏肥大信号传导介质。 TGFβ1的中和抗体减弱了条件培养基的促肥大作用，并且使用添加到新鲜培养基中的重组TGFβ1在体外复制了条件培养基的促肥大作用。这些数据表明，内皮祖细胞分泌的旁分泌因子有可能诱导心肌细胞肥大，导致梗塞区域左心室质量增加，并对心肌梗塞后的区域功能产生有利的中期影响。
Administration of endothelial progenitor cells (EPC) is a promising therapy for post-infarction cardiac repair. However, the mechanisms that underlie apparent beneficial effects on myocardial remodeling are unclear. In a porcine model of acute myocardial infarction, we investigated the therapeutic effects of a mixed population of culture modified peripheral blood mononuclear cells (termed hereafter porcine EPC). Porcine EPC were isolated using methods identical to those previously adopted for harvest of EPC in human cell therapy studies. In addition the therapeutic effects of paracrine factors secreted by these cells was evaluated in vitro and in vivo. Intracoronary injection of autologous porcine EPC was associated with increased infarct territory mass and improved regional ventricular systolic function at 2 months compared to control. Treatment with conditioned media derived from autologous EPC was associated with similar improved effects on infarct territory mass and function. Histologic analysis of the infarct territory revealed significantly increased cardiomyocyte size in EPC and conditioned media treated groups, when compared to controls. A paracrine EPC effect was also verified in a pure myocardial preparation in which cardiomyocytes devoid of fibroblast, neuronal and vascular elements directly responded by increasing cell mass when exposed to the same conditioned media. Analysis of conditioned media revealed elevated levels of TGF beta 1 (human 267.3 +/- 11.8 pg/ml, porcine 57.1 +/- 6.1 pg/ml), a recognized mediator of hypertrophic signaling in the heart. Neutralizing antibodies to TGF beta 1 attenuated the pro-hypertrophic effect of conditioned media, and use of recombinant TGF beta 1 added to fresh media replicated the pro-hypertrophic effects of conditioned media in vitro. These data demonstrate the potential of paracrine factors secreted from endothelial progenitor cells to induce cardiomyocyte hypertrophy contributing to increased infarct territory LV mass, with favorable medium term effects on regional function following myocardial infarction.